CN111961053B - Fluorescent probe of tricyclic 2-aminopyridine salt and preparation method and application thereof - Google Patents

Fluorescent probe of tricyclic 2-aminopyridine salt and preparation method and application thereof Download PDF

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CN111961053B
CN111961053B CN202010846280.3A CN202010846280A CN111961053B CN 111961053 B CN111961053 B CN 111961053B CN 202010846280 A CN202010846280 A CN 202010846280A CN 111961053 B CN111961053 B CN 111961053B
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salt
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CN111961053A (en
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唐本忠
秦安军
王柄楠
胡蓉蓉
赵祖金
王志明
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South China University of Technology SCUT
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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    • C09K2211/1025—Heterocyclic compounds characterised by ligands
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    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks

Abstract

The invention belongs to the technical field of fluorescent probes, and discloses a tricyclic 2-aminopyridine salt fluorescent probe and a preparation method and application thereof. The structure of the fluorescent probe of the tricyclic 2-aminopyridine salt is shown as a formula I, wherein: r1，R2Independently are aryl, heteroaryl, C1‑18Alkyl radical, C3‑8Electron donating groups of cycloalkyl or aromatic ring derivatives; x is a monovalent anion; m is an integer of 0 to 2; n is any integer of 0 and 1. The invention also discloses a preparation method of the fluorescent probe. The fluorescent probe has aggregation-induced emission property, can realize rapid dyeing identification of microorganisms, and embodies the characteristics of specificity, high efficiency and sensitivity. The fluorescent probe has excellent bacteriostatic effect. The fluorescent probe is used for preparing reagents for specifically dyeing mitochondria and dyeing microbes with negative charges on the surface, and is also used for preparing reagents for distinguishing the death and activity states of the microbes and antibacterial agents.

Description

Fluorescent probe of tricyclic 2-aminopyridine salt and preparation method and application thereof
Technical Field
The invention belongs to the field of biomedical materials, and particularly relates to a tricyclic 2-aminopyridine salt fluorescent probe, a preparation method thereof and application thereof in microbial marker identification and bacteriostasis.
Background
Under normal state, the microorganism and human are interdependent to maintain the balance of physiological metabolism; once the balance is broken, disease is easily caused. Bacterial infections can cause a variety of diseases and pose serious threats to human health. During the course of treatment, the diagnosis of bacteria is the first step. Currently, gram staining is mainly used, which is complicated to operate and does not allow in situ monitoring of live bacteria. Meanwhile, in the treatment process, due to the abuse of antibiotics, drug-resistant strains appear, so that the treatment difficulty is increased. Therefore, it is very important to develop accurate and rapid bacteria identification and diagnosis reagents and effective antibacterial materials.
The organic small molecular fluorescent probe is widely applied to biological imaging, biological detection and treatment, and has the characteristics of simple operation, low cost, quick detection and the like. However, the conventional fluorescent material has a problem of aggregation-induced emission quenching (ACQ) in an aggregated state due to its large pi-conjugated system; its high background fluorescence also reduces the signal-to-noise ratio during detection and diagnosis, which greatly reduces its detection sensitivity. Compared with the traditional aggregation-induced fluorescence quenching material, the fluorescent material with aggregation-induced emission (AIE) property has high luminous efficiency, large Stokes displacement, high signal-to-noise ratio and good biocompatibility in an aggregation state; such materials would greatly improve the sensitivity of detection.
The invention synthesizes the fluorescent material with good AIE property, realizes the rapid dyeing identification of microorganisms through the regulation and control of the structure, and embodies the characteristics of specificity, high efficiency and sensitivity. Meanwhile, due to the special structure of the tricyclic 2-aminopyridine salt, the antibacterial effect is excellent, and the antibacterial agent can be used as a potential antibacterial agent.
Disclosure of Invention
The invention aims to provide a tricyclic 2-aminopyridine salt fluorescent probe. The fluorescent probe has the property of Aggregation Induced Emission (AIE), can realize rapid dyeing identification on microorganisms, and embodies the characteristics of specificity, high efficiency and sensitivity. The fluorescent probe has excellent bacteriostatic effect.
Another object of the present invention is to provide a method for preparing the above fluorescent probe. The synthetic method is simple, does not need to separate intermediate products, and obtains the tricyclic 2-aminopyridine salt with high yield through one-step series reaction; meanwhile, the preparation method can realize gram-level synthesis.
It is a further object of the present invention to provide the use of the above-described fluorescent probes. The fluorescent probe is applied to preparing a bacteriostatic agent.
The fluorescent probes are useful in biological imaging as imaging agents.
The fluorescent probe can also be applied to the preparation of microbial staining and/or marking reagents,
used as a stain for microorganisms to enable identification of the microorganisms.
The fluorescent probe is applied to a specific mitochondrial stain.
The purpose of the invention is realized by the following technical scheme:
a fluorescent probe of tricyclic 2-aminopyridine salt has a structure shown in formula I:
Figure BDA0002642259030000021
wherein:
R1，R2independently are aryl, heteroaryl, C1-18Alkyl radical, C3-8Electron donating groups of cycloalkyl or aromatic ring derivatives; x is a monovalent anion; m is an integer of 0 to 2; n is any integer of 0 and 1.
The anion is iodide (I)-) Bromine ion (Br)-) Chloride ion (Cl)-) Hydroxyl ion (OH)-) Tetrafluoroborate ion (BF)4 -) Nitrate ion (NO)3 -) Hexafluorophosphate ion (PF)6 -) Lactate ion (CH)3CH(OH)COO-) Citric acid radical ion (C)5H7O5COO-)。
The anion is preferably iodide (I)-) Bromine ion (Br)-) Chloride ion (Cl)-) Hydroxyl ion (OH)-) Hexafluorophosphate ion (PF)6 -)。
The R is1，R2Each independently is preferably one of the following a-t groups:
Figure BDA0002642259030000031
wherein R 'in the same group or different groups are the same or different, and R' is preferably hydrogen, halogen (fluorine, chlorine, bromine, iodine), C1-18Alkyl radical, C1-18Alkyloxy, C1-18Alkylthio or diethylamino.
In the fluorescent probe of the tricyclic 2-aminopyridine salt, m is an integer of 0-2; n is any integer of 0 and 1, and the structure of the compound is as follows:
Figure BDA0002642259030000041
m is any integer of 0-2; n is 0, 1, preferably m is 2, n is 1.
The preparation method of the fluorescent probe comprises the following steps: when the fluorescent probe has the formula I, R1，R2The preparation method of the fluorescent probe independently and preferably selects one of the following a-k groups, and comprises the following steps:
reacting acyl chloride derivatives with alkyne derivatives under the action of a catalyst, adding amidine cyclic derivatives, continuing to react under the catalysis of Lewis acid, and performing subsequent treatment to obtain the tricyclic 2-aminopyridine salt fluorescent probe.
The acyl chloride derivative has the structure of
Figure BDA0002642259030000042
The alkyne derivative has the structure
Figure BDA0002642259030000043
The structure of the cyclic amidine derivative is
Figure BDA0002642259030000044
Reacting acyl chloride derivative with alkyne derivative to obtain derivative of alkynone, wherein the structure of the derivative of alkynone is
Figure BDA0002642259030000045
The catalyst is divalent palladium salt and monovalent copper salt; the divalent palladium salt is preferably triphenylphosphine palladium dichloride, and the monovalent copper salt is preferably cuprous iodide.
The reaction takes an organic solvent as a reaction medium. The reaction is carried out in a protective atmosphere with the addition of a basic compound.
The alkaline compound is more than one of triethylamine, potassium carbonate, pyridine and N, N-diisopropylethylamine.
The temperature of the reaction was room temperature.
The Lewis acid is aluminum chloride.
The molar ratio of the acyl chloride derivative to the alkyne derivative is 1: (0.5-2).
The molar ratio of the acyl chloride derivative to the amidine cyclic derivative is 1: (2-4).
The temperature for the continued reaction was room temperature.
When the fluorescent probe has the formula I, R1，R2When at least one is one of l to t groups,
the preparation method of the fluorescent probe comprises the following steps: reacting acyl chloride derivatives with alkyne derivatives under the action of a catalyst, adding amidine cyclic derivatives, continuing to react under the catalysis of Lewis acid, and performing subsequent treatment to obtain halogen-containing products; reacting the halogen-containing product with a boric acid compound R3-B(OH)2And reacting to obtain the tricyclic 2-aminopyridine salt fluorescent probe.
When R is2When the acyl chloride derivative is one of a-k groups, the structure of the acyl chloride derivative is
Figure BDA0002642259030000051
When R is2When the acyl chloride derivative is one of l to t groups, the structure of the acyl chloride derivative is
Figure BDA0002642259030000052
R′2Is 4-halophenyl; when R is1When the group is one of a to k, the alkyne derivative has the structure
Figure BDA0002642259030000053
When R is1When the alkynyl derivative is one of l to t groups, the structure of the alkynyl derivative is
Figure BDA0002642259030000054
R′1Is 4-halophenyl;
R1，R2when at least one is one of l to t groups, the halogen-containing product is reacted with a boric acid compound R3-B(OH)2Reaction, at this time R'1And/or R'2Middle halogen by R3Substituted, substituted radicals R3Phenyl corresponds to R1And/or R2；
The structure of the cyclic amidine derivative is
Figure BDA0002642259030000055
In the reaction of acyl chloride derivatives and alkyne derivatives, the catalyst is divalent palladium salt and monovalent copper salt; the divalent palladium salt is preferably triphenylphosphine palladium dichloride, and the monovalent copper salt is preferably cuprous iodide.
In the reaction of acyl chloride derivative and alkyne derivative, organic solvent is used as reaction medium. The reaction is carried out in a protective atmosphere with the addition of a basic compound.
The alkaline compound is more than one of triethylamine, potassium carbonate, pyridine and N, N-diisopropylethylamine.
In the reaction of the acid chloride derivative and the alkyne derivative, the temperature of the reaction is room temperature.
The Lewis acid is aluminum chloride.
The molar ratio of the acyl chloride derivative to the alkyne derivative is 1: (0.5-2).
The molar ratio of the acyl chloride derivative to the amidine cyclic derivative is 1: (2-4).
The temperature for the continued reaction was room temperature.
Halogen-containing products with boric acid compounds R3-B(OH)2During the reaction, the reaction is carried out under the conditions of a catalyst and an alkaline compound, wherein the catalyst is palladium tetratriphenylphosphine; the alkaline compound is sodium carbonate.
The reaction takes an organic solvent and water as reaction media, and the organic solvent is preferably THF. The reaction condition is heating reflux reaction for more than 10 h.
The molar ratio of the halogen-containing product to the boric acid compound is 1: (1-2.5).
After the reaction of the halogen-containing product with the boric acid compound, the system is subjected to subsequent treatment.
When X in formula I is other than CI-When other groups are used, MX and X are Cl-The fluorescent probe of the required anion is obtained; wherein M in MX is a monovalent metal ion.
Specifically, MX and X are Cl in water or an organic solvent and water-The fluorescent probe of the required anion is obtained by reaction.
In the preparation method, after the acyl chloride derivative and the alkyne derivative are reacted, the product of the alkyne ketone derivative does not need to be separated, and Lewis acid and amidine cyclic derivative are directly added into a reacted system for continuous reaction. The reaction of the present invention is a tandem reaction.
When the fluorescent probe has the formula I, R1，R2When each independently is preferably one of the above a-k groups, the reaction equation of the method for preparing the fluorescent probe is
Figure BDA0002642259030000061
The tricyclic 2-aminopyridine salt derivative constructed by the invention can realize specific dyeing with negatively charged mitochondria in cells through electrostatic adsorption. Due to the fact that the surfaces of the microorganisms are provided with negative charges and the difference of membrane structures of different microorganisms, the molecules can realize selective staining and identification of different types of microorganisms; when the microorganisms are in two different states of death and activity, the permeability of the membranes of the microorganisms can be changed, and the life states of the microorganisms can be distinguished by utilizing the change of the permeability of the membranes of the microorganisms.
The fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing a reagent for specifically dyeing mitochondria. The staining is fluorescence imaging.
The fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing a reagent for staining microorganisms with negative charges on the surface, and is used for distinguishing and identifying the microorganisms with negative charges and different charges (such as positive charges and neutrality). The staining is fluorescence imaging. The negatively charged microorganism is preferably a gram positive bacterium.
The fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing a reagent for distinguishing the dead and live state of microorganisms, wherein the distinguishing means that the living microorganisms cannot be dyed (fluorescence imaging) by the fluorescent probe, and the microorganisms can be dyed after the microorganisms die.
The invention also provides the application of the fluorescent molecular probe in bacteriostasis. Due to the structure of the special compound, the compound is found to have good adsorption effect on gram-positive bacteria in the process of microorganism identification and dyeing, and the compound is found to have good bacteriostatic ability through tests of a microorganism growth curve, minimum bacteriostatic concentration and a surface bacteriostatic experiment.
The fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing an antibacterial agent, in particular an antibacterial agent of gram-positive bacteria.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the invention synthesizes the tricyclic 2-aminopyridine salt fluorescent material with Aggregation Induced Emission (AIE) performance so as to overcome aggregation quenching effect of the traditional fluorescent material, has simple synthesis method, does not need to separate intermediate products, and obtains the tricyclic 2-aminopyridine salt with high yield through one-step series reaction; meanwhile, the preparation method can realize gram-level synthesis.
(2) The tricyclic 2-aminopyridine salt fluorescent material realizes specific targeting on mitochondria in cells.
(4) The tricyclic 2-aminopyridine salt fluorescent material can realize the identification and dyeing of different types of microorganisms by a fluorescence imaging method, and can also realize the differentiation of dead microorganisms.
(5) The tricyclic 2-aminopyridine salt fluorescent material has an obvious inhibition effect on bacteria.
Drawings
In FIG. 1 (A) is a sequence with H2Increased O content TMTAP-7 (10. mu.M) in THF/H2Normalized fluorescence emission profile in O (v/v) mixed solvent; (B) is as follows H2Increased O content DTTAP-7 (10. mu.M) in THF/H2Normalized fluorescence emission spectra in O (v/v) mixed solvent;
FIG. 2 is a co-localized image of BMTAP-7, TMTAP-7 and MitoTracker Red (mitochondrial Red dye) on HeLa cells; a1 is the bright field of the cell after the action of BMTAP-7, A2 is the bright field of the cell after the action of TMTAP-7; b1 is an image of HeLa cell staining by MitoTracker Red, B2 is an image of HeLa cell staining by MitoTracker Red, and B1 and B2 are images obtained by two experiments; (C1) images of HeLa cell staining after BMTAP-7 action, (C2) images of HeLa cell staining after TMTAP-7 action; d1 is a combined picture of A1, B1 and C1, and D2 is a combined picture of A2, B2 and C2;
FIG. 3 is a photograph of a fluorescent image of the staining of Staphylococcus aureus and Escherichia coli with BMTAP-7, TMTAP-7 and DTTAP-7, respectively; the black part of the graph is a picture under a fluorescent field, and the gray part of the graph is a picture superposed with the fluorescent field and a bright field;
FIG. 4 is a confocal microscope fluorescence image and superimposed photograph of BMTAP-7 and PI co-cultured with microorganisms; wherein, A) dead large intestine rods, B) dead cupronickel bacteria, C) dead yeasts, D) normal yeasts;
FIG. 5 is a graph showing the growth curves of BMTAP-7, TMTAP-7 and DTTAP-7 against Staphylococcus aureus and Escherichia coli, respectively, at different concentrations;
FIG. 6 is a graph showing the inhibition of Staphylococcus aureus by BMTAP-7, TMTAP-7 and DTTAP-7 in solid media at different concentrations, respectively; A1-E1 are graphs of inhibition of BMTAP-7 against Staphylococcus aureus in solid media of 0, 2, 4, 8, 16. mu.g/mL, respectively; A2-E2 are graphs of inhibition of TMTAP-7 on Staphylococcus aureus in solid culture media of 0, 2, 4, 8 and 16 mug/mL respectively; A3-E3 are graphs of DTTAP-7 inhibiting staphylococcus aureus in solid culture media of 0, 2, 4, 8 and 16 mug/mL respectively;
FIG. 7A) results of the bacteriostatic concentration test of BMTAP-7, TMTAP-7 and DTTAP-7 in the medium, respectively; B) respectively adding BMTAP-7, TMTAP-7 and DTTAP-7 into a solid culture medium, and then coating the solid culture medium with a test for the bacteriostatic effect of bacteria; C) to smear BMTAPC-7 on the surface of solid medium, the control group: BMTAPC-7 is not coated, and bacteria are directly coated; experimental groups: BMTAPC-7 was applied followed by the bacteria.
Detailed Description
The present invention will be further described with reference to the following specific examples and drawings, but the embodiments of the present invention are not limited thereto.
EXAMPLE 1 preparation of a fluorescent Probe (BMTAPC-7)
Figure BDA0002642259030000081
The synthetic route is as follows:
Figure BDA0002642259030000091
4-bromobenzoyl chloride (10mmol,2.19g), 4-methoxyphenylacetylene (10mmol,1.32g), PdCl2(PPh3)2(0.2mmol,144mg) and cuprous iodide (0.4mmol,76mg) were added to a 250mL two-necked round-bottomed flask, respectively, and then evacuated with a pump and replaced with nitrogen three times for 3 times; then dry dichloromethane (100mL), triethylamine (11mmol,1.5mL) was added; the reaction was stirred at room temperature for 5h (progress of reaction was monitored by TLC). To be reacted with a substrateCompletely, slowly adding anhydrous AlCl into the reaction system3(1mmol,133mg) and DBU (30mmol,4.5mL), stirring the reacted mixture at room temperature for 2h (TLC monitoring until the reaction is complete), removing the catalyst from the mixed reaction solution by suction filtration, concentrating the filtrate, acidifying with 20mL of 1M hydrochloric acid, and extracting with dichloromethane (60 mL. times.5); the organic phases were combined and washed with anhydrous Na2SO4Dried, concentrated, loaded and purified through a silica gel column eluting with DCM and methanol (gradient elution ratio 25:1-10:1-5:1) to give 3.49g of BMTAPC-7 as a yellow solid in 72% yield.
1H NMR(400MHz,D2O)δ7.20(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,2H),6.91–6.87(m,4H),5.86(s,1H),3.93(t,J＝5.6Hz,2H),3.72(s,3H),3.69(t,J＝5.6Hz,2H),3.46(t,J＝6.4Hz,2H),2.41(t,J＝5.6Hz,2H),2.02–1.95(m,2H),1.89–1.85(m,2H),1.56–1.51(m,2H)；13C NMR(125MHz,D2O)δ160.7,154.3,152.5,148.0,136.7,131.5,130.5,130.3,125.1,124.8,123.0,116.0,114.4,55.6,52.5,49.8,49.7,28.6,23.4,23.2,21.7。
EXAMPLE 2 preparation of a fluorescent Probe (BMTAPC-5)
Figure BDA0002642259030000092
The synthetic route is as follows:
Figure BDA0002642259030000101
4-bromobenzoyl chloride (10mmol,2.19g), 4-methoxyphenylacetylene (10mmol,1.32g), PdCl2(PPh3)2(0.2mmol,144mg) and cuprous iodide (0.4mmol,76mg) were added to a 250mL two-necked round-bottomed flask, respectively, and then evacuated with a pump and replaced with nitrogen three times for 3 times; then dry dichloromethane (100mL), triethylamine (11mmol,1.5mL) were added and the reaction stirred at room temperature for 5h (monitoring the progress of the reaction by TLC) and, until the substrate was completely reacted, anhydrous AlCl was slowly added to the reaction system3(1mmol,133mg) and DBN (30mmol,4.5 mL). Mixing of reactionsThe solution was stirred at room temperature for 2h (TLC monitoring was done until the reaction was complete), the combined reaction solution was filtered off by suction to remove the catalyst, the filtrate was concentrated, acidified with 20mL of 1M hydrochloric acid and extracted with dichloromethane (60 mL. times.5). The organic phases were combined and washed with anhydrous Na2SO4Dried, concentrated, loaded and purified through a silica gel column eluting with DCM and methanol (gradient elution ratio 25:1-10:1-5:1) to give 2.65g of BMTAPC-5 as a yellow solid in 58% yield.
1H NMR(400MHz,D2O)δ7.49(d,J＝8.0Hz,2H),7.16–7.18(m,4H),6.99(d,J＝8.0Hz,2H),5.94(s,1H),4.70–3.78(m,7H),3.41(t,J＝5.6Hz,2H),3.04(t,J＝7.6Hz,2H),1.94–1.99(m,2H).13C NMR(125MHz,D2O)δ160.4,154.6,145.8,142.9,133.9,131.9,130.4,129.3,124.9,123.8,123.8,114.3,113.6,55.5,51.9,45.8,42.0,25.0,18.5。
EXAMPLE 3 preparation of a fluorescent Probe (BMTAP-7)
Figure BDA0002642259030000102
The synthetic route is as follows:
Figure BDA0002642259030000111
solid BMTAPC-7(1mmol,485mg) synthesized in example 1 was dissolved in acetone, aqueous potassium hexafluorophosphate (2mmol,368mg) was added, stirred for 2h, the mixture was added with water and then filtered, and the filtered solid was washed with water to remove inorganic salts and dried to give 535mg of BMTAP-7 as a yellow solid in 90% yield.
EXAMPLE 4 preparation of a fluorescent Probe (TMTAP-7)
Figure BDA0002642259030000112
The synthetic route is as follows:
Figure BDA0002642259030000113
(1) synthesis of intermediate BMTAPC-7 was carried out in the same manner as in example 1
(2) Under nitrogen, the compound BMTAPC-7(1mmol,485mg), triphenylamine borate (1.2mmol,347mg), tetrakistriphenylphosphine palladium (0.05mmol,58mg) and sodium carbonate (1.5mmol,207mg) were charged in a two-necked flask, and the mixture was added in THF-H2O (10mL-10mL), heated at reflux for 12h (progress of reaction monitored by TLC thin layer chromatography), after completion of the reaction, the reaction was cooled to room temperature and then extracted with ethyl acetate (40 mL. times.3), all organic layers were combined and washed with anhydrous Na2SO4Drying, concentrating, and purifying with silica gel column using DCM and MeOH (25:1) as eluent to give a yellow solid; the solid was then dissolved in acetone, and aqueous potassium hexafluorophosphate (2mmol,368mg) was added and stirred for 2 h. The mixture was filtered through water, and the filtered solid was washed with water to remove inorganic salts and dried to give 531mg of TMTAP-7 as a yellow solid in 70% yield.
1H NMR(400MHz,DMSO-d6)δ7.79(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz,2H),7.57(d,J＝8.0Hz,2H),7.35(t,J＝8.0Hz,4H),7.15(d,J＝8.0Hz,2H),7.12–7.04(m,8H),6.85(s,1H),4.07–4.04(m,2H),3.86–3.83(m,5H),3.51(t,J＝6.0Hz,2H),2.86–2.83(m,2H),2.20–2.14(m,2H).2.04–1.97(m,2H),1.88–1.81(m,2H).13C NMR(100MHz,DMSO-d6)δ161.1,154.6,154.2,148.2,147.7,147.3,141.2,136.1,133.0,131.3,130.1,130.1,128.3,126.8,125.4,125.0,124.9,124.0,123.3,117.1,114.9,55.9,52.2,49.9,49.6,29.5,23.6,23.5,22.1。
EXAMPLE 5 preparation of a fluorescent Probe (DTTAP-7)
Figure BDA0002642259030000121
The synthetic route is as follows:
Figure BDA0002642259030000131
4-bromobenzoyl chloride (10mmol,2.19g), 4-bromophenylacetylene (10mmol,1.81g), PdCl2(PPh3)2(0.2mmol,144mg) and cuprous iodide (0.4mmol,76mg) were added to a 250mL two-necked round-bottomed flask, respectively, and then evacuated with a pump and replaced with nitrogen three times for 3 times; then dry dichloromethane (100mL), triethylamine (11mmol,1.5mL) were added and the reaction stirred at room temperature for 5h (reaction progress was monitored by TLC); when the substrate is completely reacted, slowly adding anhydrous AlCl into the reaction system3(1mmol,133mg) and DBU (30mmol,4.5mL), the reaction mixture was stirred at room temperature for 2h (TLC monitoring was done until the reaction was complete), the reaction mixture was filtered off the catalyst by suction, the filtrate was concentrated, acidified with 1M hydrochloric acid (20 mL), extracted with dichloromethane (60 mL. times.5), the organic phases were combined and washed with anhydrous Na2SO4Drying, concentrating, loading, and purifying with silica gel column using DCM and methanol as eluent (gradient elution ratio is 25:1-10:1-5: 1). Finally, 3.63g of DBTAPC-7 was obtained as a yellow solid in a yield of 68%.
Under nitrogen, the compound DBTAPC-7(1mmol,534mg), triphenylamine borate (1.2mmol,347mg), tetrakistriphenylphosphine palladium (0.1mmol,106mg) and sodium carbonate (3.0mmol,414mg) were charged in a two-necked flask, and the mixture was added in THF-H2O (10mL-10mL), heated at reflux for 12h (progress of reaction monitored by TLC thin layer chromatography), after completion of the reaction, the reaction was cooled to room temperature and then extracted with ethyl acetate (40 mL. times.3), all organic layers were combined and washed with anhydrous Na2SO4Drying, concentrating, and purifying with silica gel column using DCM and MeOH (25:1) as eluent to give a yellow solid; then the solid was dissolved in acetone, an aqueous solution of potassium hexafluorophosphate (2mmol,368mg) was added thereto, stirred for 2 hours, the mixture was filtered with water, the filtered solid was washed with water to remove inorganic salts, and dried to obtain 418mg of DTTAP-7 as a tan solid in 43% yield.
1H NMR(400MHz,DMSO-d6)δ7.86(d,J＝8.0Hz,2H),7.80(d,J＝8.0Hz,2H),7.71–7.63(m,8H),7.37–7.33(m,8H),7.13–7.05(m,16H),6.94(s,1H),4.10(t,J＝5.2Hz,2H),3.87(t,J＝5.2Hz,2H),3.54(t,J＝6.4Hz,2H),2.87(t,J＝5.2Hz,2H),2.23–2.17(m,2H),2.04–1.98(m,2H).1.90–1.82(m,2H),13C NMR(125MHz,DMSO-d6)δ154.2,153.7,147.5,147.4,147.3,146.9,146.8,141.3,140.7,135.6,132.6,132.3,131.1,129.9,129.7,129.7,127.8,127.8,126.5,126.4,124.8,124.5,124.4,123.6,123.5,122.8,122.6,116.6,51.8,49.5,49.2,29.1,23.1,23.0,21.6。
EXAMPLE 6 AIE characterization of fluorescent probes for tricyclic 2-aminopyridinium salts
FIG. 1 is a fluorescence spectrum of TMTAP-7 based on the materials obtained in example 4 and example 5, respectively, under different water content conditions. When the two molecules are in tetrahydrofuran solution, the luminescence is weaker, the fluorescence intensity can be continuously enhanced along with the addition of water, and the fluorescence intensity reaches the maximum when the water content reaches 99 percent. This is due to the increase in fluorescence as the molecules aggregate with the addition of poor solvent water. These results demonstrate good Aggregation Induced Emission (AIE) properties of these molecules.
EXAMPLE 7 targeting of fluorescent probes for tricyclic 2-aminopyridinium salts to mitochondria
FIG. 2 is a graph of the targeted fluorescence imaging of BMTAP-7 and TMTAP-7 on organelle mitochondria. After HeLa cells were cultured for 24 hours, 2. mu.M MTAP-7 and 100nm MitoTracker Red (mitochondrial Red fluorescent Probe) were added to the medium. Then the mixture is acted for 30 minutes in an incubator at 37 ℃ and is imaged and characterized by a laser confocal microscope. The imaging procedure for TMTAP-7 was the same as for BMTAP-7. From the imaging results, it was found that these molecules, due to their positive charge, can interact with the mitochondrial membrane, which is negatively charged, thereby achieving specific adsorption. The coincidence of BMTAP-7 and TMTAP-7 with the commercial dye MitoTracker Red was very high, up to 91% and 93%, respectively.
Example 8 application of fluorescent probes to Tricyclo 2-aminopyridinium salts to staining and identification of microorganisms
FIG. 3 is a photograph showing the results of imaging the staining of Staphylococcus aureus (gram-positive bacteria) and Escherichia coli (gram-negative bacteria) with BMTAP-7, TMTAP-7 and DTTAP-7 (fluorescence imaging photograph). Respectively reacting BMTAP-7, TMTAP-7 and DTTAP-7 with 5 μ M concentration to Staphylococcus aureus or Escherichia coli with OD concentration6000.1, at 3After incubation in an incubator at 7 ℃ for 20min, the cells were collected and observed under a laser confocal microscope after centrifugation at 7100rpm for 2 min. Among the two bacteria, this class of molecules has good stainability towards Staphylococcus aureus. From the aspect of staining effect, the molecules can achieve uniform staining on staphylococcus aureus.
The results of the staining and identification of microorganisms in different states by BMTAP-7 are shown in FIG. 4. FIG. 4 is a confocal microscope fluorescence image and superimposed photograph of BMTAP-7 and PI co-cultured with microorganisms; wherein A) dead large intestine rods, B) dead Pseudomonas aeruginosa, C) dead yeasts, and D) normal yeasts. After treating various kinds of microorganisms with 75% ethanol for 20 minutes, after washing three times with PBS, BMTAP-7 at a concentration of 5. mu.M and propidium iodide at a concentration of 3. mu.g/mL were allowed to act on dead microorganisms, and after 20 minutes in an incubator at 37 ℃, the cells were collected after centrifugation at 7100rpm for 2 minutes and observed under a confocal laser microscope. It can be seen that E.coli originally in a live state is hardly stained, while E.coli in a dead state is easily stained. We have found by co-staining with Propidium Iodide (PI) that this class of molecules functions similarly to propidium iodide. It is found from graph D in FIG. 4 that it is difficult to stain for live yeasts, and easier for dead yeasts. It is disclosed that such molecules can be used to distinguish different states of a microorganism.
Example 9 inhibition of bacteria by fluorescent probes of tricyclic 2-aminopyridinium salts
(1) Testing of bacterial growth curves
Subjecting Staphylococcus aureus or Escherichia coli OD600Approximately 0.1 was co-cultured with BMTAP-7, TMTAP-7 and DTTAP-7 at concentrations of 0.5, 1, 2, 4, 8, 16, 32, 64. mu.M, respectively, and incubated at 37 ℃ in a shaker incubator at 180 rpm. The OD of the bacteria was measured every 2 hours with a microplate reader600The value is obtained. The test result is shown in figure 5, the compound has obvious inhibiting effect on staphylococcus aureus, and the BMTAP-7 and TMTAP-7 show good bacteriostatic effect at the concentration of 4 mu M and higher.
(2) Testing of bacteriostatic experiments
Minimal inhibition of BMTAP-7, TMTAP-7 and DTTAP-7And (4) measuring the concentration of bacteria. 100. mu.L of bacterial suspension (1X 10)6CFU/mL) was added to a broth of BMTAP-7, TMTAP-7 and DTTAP-7 at a concentration of from 0. mu.g/mL to 16. mu.g/mL. OD measurement by microplate reader600Value, incubated in an incubator at 37 ℃ for 24 hours, after which OD was again measured600The value is obtained. The inhibition rate was calculated. The test results are shown as a in fig. 7. From A in FIG. 7, it can be seen that the molecules BMTAP-7 and TMTAP-7 exhibited good inhibitory effects in the culture medium, and their minimum inhibitory concentrations were between 4. mu.g/mL and 8. mu.g/mL.
BMTAP-7, TMTAP-7 and DTTAP-7 were added to hot NB medium, respectively, and then cooled to form agar plates at concentrations from 0. mu.g/mL to 16. mu.g/mL. OD reduction with PBS6000.5 bacterial solution serial dilution 5X 105And (4) doubling. Bacterial suspensions (100. mu.L) were dropped into agar plates of different concentrations. Then, the bacterial liquid is uniformly dispersed by a coating rod. Then, the agar plate is placed in an incubator at 37 ℃ and incubated for 24 hours, and the bacteriostasis rate is counted and calculated. As a result, as shown in FIG. 6 and B in FIG. 7, it was found that no colonies were found on the plate at a concentration of 8. mu.g/mL of the molecule BMTAP-7. And a good antibacterial effect is shown.
FIG. 7C is a comparison graph of the bacteriostatic effect of BMTAPC-7 coated on the surface of solid medium. By first applying the molecule BMTAPC-7 to the surface of a solid medium and then applying the bacteria to the surface. The control group was not coated with the antimicrobial molecule BMTAPC-7. As can be seen from the results, such molecules have the ability to be surface contact antimicrobial, and the effect of inhibiting bacteria is achieved through surface contact.
FIG. 6 is a graph showing the inhibition of Staphylococcus aureus by BMTAP-7, TMTAP-7 and DTTAP-7 in solid media at different concentrations, respectively; A1-E1 are graphs of inhibition of BMTAP-7 against Staphylococcus aureus in solid media of 0, 2, 4, 8, 16. mu.g/mL, respectively; A2-E2 are graphs of inhibition of TMTAP-7 on Staphylococcus aureus in solid culture media of 0, 2, 4, 8 and 16 mug/mL respectively; A3-E3 are graphs of DTTAP-7 inhibiting staphylococcus aureus in solid culture media of 0, 2, 4, 8 and 16 mug/mL respectively;
FIG. 7A) results of the bacteriostatic concentration test of BMTAP-7, TMTAP-7 and DTTAP-7 in the medium, respectively; B) respectively adding BMTAP-7, TMTAP-7 and DTTAP-7 into a solid culture medium, and then coating the solid culture medium with a test for the bacteriostatic effect of bacteria; C) to smear BMTAPC-7 on the surface of solid medium, the control group: BMTAPC-7 is not coated, and bacteria are directly coated; experimental groups: BMTAPC-7 was applied followed by the bacteria.

Claims (8)

1. A fluorescent probe of tricyclic 2-aminopyridine salt is characterized in that: the structure is formula I:
Figure FDA0003357175920000011
wherein:
x is a monovalent anion; m is 2, n is 1;
the anion is I-、Br-、Cl-、OH-、PF6 -；
R1，R2Each independently is one of the following g, h, n groups:
Figure FDA0003357175920000012
r' in the group g is halogen; r' in the group h is C1-18An alkyl group; r' in the n group is hydrogen.
2. The method for preparing a tricyclic 2-aminopyridine salt fluorescent probe according to claim 1, characterized in that: comprises the following steps:
reacting acyl chloride derivatives with alkyne derivatives under the action of a catalyst, adding amidine cyclic derivatives, continuing to react under the catalysis of Lewis acid, and performing subsequent treatment to obtain a tricyclic 2-aminopyridine salt fluorescent probe;
the acyl chloride derivative has the structure of
Figure FDA0003357175920000013
The alkyne derivative has the structure
Figure FDA0003357175920000014
The structure of the cyclic amidine derivative is
Figure FDA0003357175920000015
R1，R2Each independently is one of the following g, h groups:
Figure FDA0003357175920000021
r' in the group g is halogen; r' in the group h is C1-18An alkyl group;
by the preparation method, the anion in the fluorescent probe of the tricyclic 2-aminopyridine salt is Cl-As fluorescent probe containing chlorine;
when the anion in the structure of the fluorescent probe of the tricyclic 2-aminopyridine salt is Cl-When other groups are used, MX and the chlorine-containing fluorescent probe are used for acting to obtain the fluorescent probe of the needed anion; wherein M in MX is a monovalent metal ion, and X is an anion.
3. The method for preparing a tricyclic 2-aminopyridine salt fluorescent probe according to claim 2, characterized in that: the catalyst is divalent palladium salt and monovalent copper salt;
the reaction takes an organic solvent as a reaction medium; the reaction is carried out under a protective atmosphere and with the addition of a basic compound; the alkaline compound is more than one of triethylamine, potassium carbonate, pyridine and N, N-diisopropylethylamine;
the temperature of the reaction is room temperature;
the Lewis acid is aluminum chloride;
the molar ratio of the acyl chloride derivative to the alkyne derivative is 1: (0.5 to 2);
the molar ratio of the acyl chloride derivative to the amidine cyclic derivative is 1: (2-4);
the temperature for the continued reaction was room temperature.
4. The method for preparing a tricyclic 2-aminopyridine salt fluorescent probe according to claim 1, characterized in that: r in fluorescent probes1，R2When at least one is an n group, the method comprises the following steps:
reacting acyl chloride derivatives with alkyne derivatives under the action of a catalyst, adding amidine cyclic derivatives, continuing to react under the catalysis of Lewis acid, and performing subsequent treatment to obtain halogen-containing products; reacting the halogen-containing product with a boric acid compound R3-B(OH)2Reacting to obtain a tricyclic fluorescent probe of 2-aminopyridine salt;
when R is2When one of the groups g and h is adopted, the acyl chloride derivative has the structure
Figure FDA0003357175920000022
When R is2When the acyl chloride derivative is one of n groups, the structure of the acyl chloride derivative is
Figure FDA0003357175920000031
R′2Is 4-halophenyl; when R is1When one of the groups g and h is adopted, the alkyne derivative has the structure
Figure FDA0003357175920000032
When R is1When it is an n group, the alkyne derivative has the structure
Figure FDA0003357175920000033
R′1Is 4-halophenyl;
R1，R2with the halogen-containing product and the boric acid compound R when at least one is an n group3-B(OH)2Reaction, at this time R'1And/or R'2Middle halogen by R3Substituted, substituted radicals R3Phenyl corresponds to R1And/or R2；
R3Is composed of
Figure FDA0003357175920000034
The structure of the cyclic amidine derivative is
Figure FDA0003357175920000035
One of the g, h, n groups:
Figure FDA0003357175920000036
r' in the group g is halogen; r' in the group h is C1-18An alkyl group; r' in the n group is hydrogen;
by the preparation method, the anion in the fluorescent probe of the tricyclic 2-aminopyridine salt is Cl-As fluorescent probe containing chlorine;
when the anion in the structure of the fluorescent probe of the tricyclic 2-aminopyridine salt is Cl-When other groups are used, MX and the chlorine-containing fluorescent probe are used for acting to obtain the fluorescent probe of the needed anion; wherein M in MX is a monovalent metal ion, and X is an anion.
5. The method for preparing a tricyclic 2-aminopyridine salt fluorescent probe according to claim 4, characterized in that: in the reaction of acyl chloride derivatives and alkyne derivatives, the catalyst is divalent palladium salt and monovalent copper salt;
in the reaction of acyl chloride derivative and alkyne derivative, organic solvent is used as reaction medium in the reaction; the reaction is carried out under a protective atmosphere and with the addition of a basic compound; the alkaline compound is more than one of triethylamine, potassium carbonate, pyridine and N, N-diisopropylethylamine;
in the reaction of acyl chloride derivative and alkyne derivative, the temperature of the reaction is room temperature;
the Lewis acid is aluminum chloride;
the molar ratio of the acyl chloride derivative to the alkyne derivative is 1: (0.5 to 2);
the molar ratio of the acyl chloride derivative to the amidine cyclic derivative is 1: (2-4);
the temperature for the continuous reaction is room temperature;
halogen-containing products with boric acid compounds R3-B(OH)2When reacting, the reaction is carried out under the conditions of a catalyst and a basic compound; the reaction takes an organic solvent and water as reaction media;
the molar ratio of the halogen-containing product to the boric acid compound is 1: (1-2.5).
6. Use of a tricyclic 2-aminopyridine salt fluorescent probe according to claim 1, characterized in that: the fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing a reagent for specifically dyeing mitochondria; the staining is selective fluorescence imaging of mitochondria.
7. Use of a tricyclic 2-aminopyridine salt fluorescent probe according to claim 1, characterized in that: the fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing a reagent for staining microorganisms with negative charges on the surface, and is used for distinguishing and identifying the microorganisms with different negative charges and charities;
the fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing a reagent for distinguishing the death and activity states of microorganisms, wherein the distinguishing refers to that the living microorganisms cannot be dyed by the fluorescent probe, and the microorganisms are dyed after the microorganisms die.
8. Use of a tricyclic 2-aminopyridine salt fluorescent probe according to claim 1, characterized in that: the fluorescent probe of the tricyclic 2-aminopyridine salt is used for preparing the antibacterial agent.
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